Evidence from multiple sources implicates dysfunction in distributed cortical networks in individuals with schizophrenia, defined both by aberrant activation provoked by defined cognitive tasks and by associated abnormal correlation of activity between different nodes in the activated network. These abnormal over- or underactivations are hypothesized to vary in response to task type and difficulty level, and to current symptom profile. The overall aim of this competitive renewal of RO1 MH 43755 "Quantitative Structural Neuroimaging in Psychosis" is to build on data gathered in the prior years of this grant that implicated dysfunction of the heteromodal association neocortical network (HASC) as playing a central role in the pathophysiology of schizophrenia, to better define and understand this dysfunction. This proposal combines expertise in clinical assessment, fMRI task development and data analysis, cognitive assessment and detailed quantitative structural brain measurement. Prior versions of the proposal examined structural HASC abnormalities in relationship to psychotic symptoms using MRI morphometry. The current work utilizes functional MRI (fMRI) to dissect HASC dysfunction using a comprehensive battery of well-characterized cognitive activation paradigms, where task performance can be characterized both inside and outside the scanner. We propose to examine a diverse population of 100 symptomatically, functionally and cognitively well-assessed patients with SZ on stable doses of second-generation anti-psychotic medications, compared to 100 matched, exceptionally well characterized healthy control subjects. These latter are participating in an ongoing representative population study of usual aging, drawn from the same catchment areas as our patients. In addition to assessing fMRI activation patterns gathered using 3 cognitive probe tasks that activate different nodes in the HASC network, we will measure volumes of the same brain regions using MRI morphometry, to explore structure/function relationships correctively. We will also examine fMRI task-uncorrelated synchrony patterns to address possible between-group performance differences. These data will be entered into structural equation models to permit a thorough examination of multiple aspects of HASC brain dysfunction in SZ and explore how brain structure and function abnormalities relate to putative underlying symptomatically- and cognitively-defined subtypes.